Abstract
Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48–2.12, P = 5.35 × 10−10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50–2.27, P = 4.34 × 10−9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72–3.16, P = 4.21 × 10−8). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.
Highlights
Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC)
When combining the results from the discovery and replication stages, we identified three low-frequency coding variants that were significantly associated with the risk of PDAC and displayed P values reaching genome-wide significance by an additive model in logistic regression analysis (Table 1 and Supplementary Table 4)
The most significant association was noted for rs34309238, which is located in the 11th exon of protein kinase N1 (PKN1) in chromosome 19p13.12 (OR = 1.77, 95% confidence interval (CI) 1.48–2.12, P = 5.35 × 10−10) by an additive model in logistic regression analysis
Summary
Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease. Further functional analyses show that the PKN1 rs34309238 variant increases the level of phosphorylated PKN1 and enhances cells' proliferation by phosphorylating and activating the focal adhesion kinase (FAK)/ phosphatidylinositol-3 kinase (PI3K)/AKT signalling pathway These findings highlight the significance of low-frequency missense variants in the development of PDAC and provide more insights into the prevention of this disease
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